Despite insulin being available as an injectable treatment for diabetes mellitus since the 1920's, diabetes continues to be a chronic public health issue. Thus, intense research continues to find alternative treatments for diabetes and related metabolic disorders. In recent years, considerable research effort has been focused on incorporating glucagon-like peptide-1 (GLP-1) into a viable treatment for diabetes. GLP-1 is secreted by ileal L cells. Secretion is dependent upon the presence of nutrients in the lumen of the small intestine. GLP-1 is a potent anti-hyperglycemic hormone. Additionally, GLP-1 is known to inhibit pancreatic β-cell apoptosis and stimulate the proliferation and differentiation of insulin-secreting β-cells. It is secreted as a pro-protein, which is then post-translationally modified to yield two physiologically active forms: GLP-1(7-37) and GLP-1(7-36)-NH2.
GLP-1(7-36)-NH2 is a polypeptide having 30 amino acid residues (residues 7-36 of the proglucagon precursor), with a primary amide (NH2) bonded to the carboxy terminus. GLP-1(7-37) is a polypeptide having 31 amino acid residues (residues 7-37 of the proglucagon precursor). Both versions have the same insulinotropic hormone secretion action. For a discussion of GLP-1 and the functionally related insulinotropic hormones extendin-3 and extendin-4, see U.S. Pat. No. 5,424,286, issued Jun. 13, 1995 to John Eng.
GLP-1 is the natural agonist for GLP-1R, a G protein-coupled receptor (GPCR) that is displayed on the surface of pancreatic β cells. Activation of GLP-1R augments glucose-dependent insulin release from β cells and, as noted above, promotes β cell survival. These properties are attractive for treatment of type 2 diabetes. However, GLP-1 is rapidly degraded by peptidases in vivo. Its half-life in vivo is less than two (2) minutes. Efforts to develop small-molecule agonists of GLP-1R have not been successful, presumably because receptor activation requires contact over an extended surface. All non-natural GLP-1R agonists reported to date consist exclusively of α-amino acid residues. In the non-natural GLP-1R agonists now known, in vivo activity is prolonged via several approaches, such as varying the sequence of α-amino acid residues, incorporating stabilizing appendages, and/or utilizing specialized delivery strategies. GLP-1 derivatives have been approved for sale for use in humans in the United States. See, for example, Victoza®-brand liraglutide (rDNA origin) for injection, marketed commercially by Novo Nordisk, Inc., Plainsboro, N.J. See also U.S. Pat. Nos. 6,268,343; 6,458,924; 7,235,627; and 8,114,833.
As used herein, the term “diabetes mellitus” or simply “diabetes” is used in a very broad sense to encompass metabolic disorders in which a subject has high blood sugar (i.e., hyperglycemia). Hyperglycemic conditions have various etiologies, such as because the pancreas does not produce enough insulin, or because cells do not respond to the insulin that is produced. There are several recognized sub-types of diabetes, some of which are better understood than others. Type 1 diabetes is characterized by the complete failure of the body to produce insulin or the failure of the body to produce enough insulin. Type 2 diabetes generally results from insulin resistance, a condition in which cells fail to use insulin properly. Type 2 diabetes sometimes co-presents with an insulin deficiency. Gestational diabetes occurs when pregnant women without a previous diagnosis of diabetes develop hyperglycemia. Less common forms of diabetes include congenital diabetes (due to genetic defects relating to insulin secretion), cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes (also known as maturity onset diabetes of the young). These last two terms are catch-all phrases that refer to several hereditary forms of diabetes caused by mutations in a single, autosomal dominant gene (as contrasted to more complex, polygenic etiologies resulting in hyperglycemia).